Nearly 11% (approximately 225,000 a year) of all pregnancies in the United States result in pre-term delivery. Such a record results in a significant incidence of perinatal morbidity and mortality. Despite major advances in neonatal care, retention of the fetus in utero is preferred in most instances. However, the desire to prolong intrauterine development must be balanced against the risks of continued pregnancy to both the mother and fetus, as well as the risks of concurrently available forms of pharmacological intervention. In general, the use of tocolytic agents to prolong pregnancy is reserved for those cases where the gestational age is greater than 20 weeks and less than 34 to 36 weeks.
There are several indications for, and contraindications to, the clinical use of agents that inhibit labor by inhibiting uterine contractions. The clearest indications for such agents are (1) to delay or prevent premature parturition in selected individuals and (2) to slow or arrest delivery for brief periods in order to undertake other therapeutic measures. Tocolytic agents that are currently in use for inhibiting contractions include .beta..sub.2 -adrenergic agonists, magnesium sulfate, ethanol, and inhibitors of prostaglandin synthesis, such as indomethacin. The use of tocolytic agents has been reviewed in several symposia (Symposium, 1981, 1982) and by Caritis (1983).
In the current practice of obstetrics, the use of indomethacin, which is an enzyme inhibitor, to inhibit prostaglandins in the treatment of premature labor prior to 33 weeks of gestation, is an accepted medical practice. However, enzyme inhibitors of prostaglandin synthesis, such as indomethacin, can unnecessarily prolong gestation in term pregnancies. In addition, the use of indomethacin in premature labor has been curtailed because of concern for its potential for causing adverse effects in the fetus. Of particular importance is the possibility of premature closure of the ductus arteriosus and the production of pulmonary hypertension from use of indomethacin. In addition, relatively high molar concentrations of indomethacin are necessary to produce pharmacological affects, on the order to at least 10.sup.-3 molar (M).
For example, the indiscriminate inhibition of several vasodilatory and vasoconstrictive prostanoids by indomethacin (prostaglandin E.sub.2, prostaglandin F.sub.2.alpha., prostacyclin, thromboxane A.sub.2) is believed to be related to the incidence of serious complications to mother and fetus from the use of this agent in vivo. For example, inhibition of prostacyclin in the pregnant animal can result in vasoconstriction; while inhibiting PGE.sub.2 can result in premature closure of the fetal ductus arteriosus. While fetal echocardiography can detect early signs of constriction of the ductus arteriosus, and its use may permit the continued administration of indomethacin or related agents in those instances where evidence of ductal construction is absent (Moise et al., 1988), the risk of these serious side effects make the treatment undesirable. The potentially serious side affects observed with currently employed regimens for managing labor, particularly with the use of indomethacin through the control of prostaglandin synthesis, continues to prompt research efforts to identify the mechanisms involved in the onset and progression of labor.
Prostanoids are a family of autacoids (formed from arachidonic acid) thought to play an important role during implantation, in the progress and maintenance of pregnancy, and during the initiation and progress of labor (Angle and Johnston, 1990). Placental prostanoid production is considered to be important during labor as well as throughout pregnancy, in regulating vascular tone, as well as affecting other hormonal production (Myatt, 1990). In human pregnancy, multiple sites of chorionic prostanoid production have been identified, i.e., the amnion, the chorion, the decidua and the placenta (Duchesne et al., 1978; Mitchell et al., 1978a, 1978b, 1978c; Robinson et al., 1979; Haning et al., 1982; Olson et al., 1983; Harper et al., 1983; Siler-Khodr et al., 1986b). In addition to its role in prostanoid production, the placenta also has multiple paracrine and endocrine capacities in human pregnancy. Although it is recognized that prostanoids such as prostaglandin E.sub.2, prostaglandin F.sub.2.alpha., the metabolite of PGF.sub.2.alpha., 13,14-dihydro-, 15-keto-prostaglandin F.sub.2.alpha. (PGFM), thromboxane A.sub.2 (TxB.sub.2) and prostacyclin (PGI.sub.2) are all produced by placental tissue, the quantities of these substances, relative to the size of the placenta is frequently not appreciated. In addition, while the placenta is known to be an important site of prostanoid production, little is known of factors controlling the production of these prostanoids from human placental tissues.
Abnormal placental prostanoid production has been reported in diseases of pregnancy, including pregnancy-induced hypertension and intra-uterine growth retardation (Demers and Gabbe, 1976; Robinson et al., 1979; Hillier and Smith, 1981; Valenzuela and Bodhke, 1980; Jogee et al., 1983; Walsh, 1985). One of the multiple causes of intrauterine growth retardation (IUGR) is defective uteroplacental perfusion (Arias and Tomich, 1982). The placenta in pregnancies complicated by IUGR may show a maternal defect in the vascular response to placentation, even without hypertensive disease (Khong et al., 1986). Although the control of placental blood flow in normal pregnancy is not well understood, placental prostanoids are thought to play a role in local vaso-regulation (Magness and Rosenfeld, 1992). However, very few studies have been done on the control of human placental prostanoid release.
Insulin-like growth factor (IGF-I), also commonly known as somatomedin-C, is a growth factor that is well known for its stimulation of cellular proliferation, and is recognized as the principal mediator of the action of growth hormone. (Murphy et al., 1990). The IGFs are known to circulate in relatively high concentrations in the body, despite the fact that they are synthesized in many, if not most, tissues. The known activity of IGF-I in mediating growth hormone is consistent with the observation made by others that it may enhance fetal growth. IGF-I has not been described as important in vasoregulation, pregnant or non-pregnant, or in regulating placental vasoregulation or vasoconstriction, and therefore, the use of IGF-I for hypertension has not been examined. In addition, in cases of IUGR, the use of IGF-I for vasoregulation of the placenta has not been examined. Neither has IGF-I been described as important in the onset or during the progression of labor, and therefore, the use of IGF-I during labor has also not been examined. Nor has IGF-I been described as related to the activity of prostaglandins or prostanoids.